The synthesis of 4-Arylsulfanyl-Substituted Kainoid analogues from trans-4-Hydroxy-L-proline

Article abstract of DOI:10.1016/S0960-894X(00)00352-8

The potent neuroexcitatory activity of kainoid amino acids in the mammalian CNS places new analogues in high demand as tools for neuropharmacological research. A range of 4-arylsulfanyl-substituted kainoids has been synthesised in a parallel fashion via mesylate displacement by a number of aromatic and heteroaromatic thiolates upon (2S,3S,4R)-1-benzoyl-3-tert-butoxycarbonylmethyl-4-methanesulfony loxy pyrrolidine-2-carboxylic acid methyl ester 8, which is obtainable in eight steps from trans-4-hydroxy-L-proline 5. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00352-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1927±1929
The Synthesis of 4-Arylsulfanyl-Substituted Kainoid Analogues
from trans-4-Hydroxy-L-proline
Jack E. Baldwin,* Gareth J. Pritchardy and Douglas S. Williamson
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 14 April 2000; revised 16 June 2000; accepted 19 June 2000
AbstractÐThe potent neuroexcitatory activity of kainoid amino acids in the mammalian CNS places new analogues in high
demand as tools for neuropharmacological research. A range of 4-arylsulfanyl-substituted kainoids has been synthesised in a
parallel fashion via mesylate displacement by a number of aromatic and heteroaromatic thiolates upon (2S,3S,4R)-1-benzoyl-3-tert-
butoxycarbonylmethyl-4-methanesulfonyloxy pyrrolidine-2-carboxylic acid methyl ester 8, which is obtainable in eight steps from
trans-4-hydroxy-l-proline 5. # 2000 Elsevier Science Ltd. All rights reserved.
The kainoids are a class of non-proteinogenic amino
acids, which have been isolated from a number of marine
and fungal sources.1 Both their intriguing general
structure 1, and broad spectrum of biological activity
provide the impetus for their study. As well as insecticidal
and anthelmintic properties,2 they have been shown to
display powerful neuroexcitatory activity in the mam-
malian central nervous system, by acting at the kainate
sub-class of ionotropic glutamate receptors.3 Structure±
activity studies4 performed on the parent compound,
kainic acid 25 and also acromelic acid A 36 have estab-
lished the main criteria for bioactivity; the most potent
analogue disclosed thus far being compound 4.7 Since
this observation was made, several other syntheses of
phenylkainoids have been published.8 Recent e€orts
within this laboratory have focussed on developing
methodology for the synthesis of further analogues of the
phenylkainoids, in a manner that may be applicable to
parallel synthesis.9 In this letter, we report the synthesis of
a novel class of 4-arylsulfanyl substituted kainoids based
on the cheap and readily available trans-4-hydroxy-l-
proline 5, a by-product of collagen hydrolysis.
ketone 6 with sodium borohydride in methanol a€orded
the alcohol 7 as a single diastereomer,{ indicating that
hydride attack had occurred from the face of the car-
bonyl group unhindered by the 2-C ester substituent.
The resulting alcohol 7 was reacted with methanesul-
fonyl chloride and triethylamine in dichloromethane,
which a€orded the mesylate 8x (mp 132±133 ꢀC, [a]d
82 (c 0.25, CH2Cl2)) in 91% yield over two steps.
It was envisaged that the mesylate 8 could undergo SN2
displacement by appropriate nucleophiles, thus setting
up the desired kainoid stereochemistry around the pyr-
rolidine ring. We noted, however, the ®ndings of the
Shirahama group,11 who described an example in which
a tosylate attached to a kainoid core was displaced by
lithium phenyl cuprate with retention of con®guration.
Additionally, Young et al.12 had unsuccessfully attempted
displacement of a mesylate by Grignard reagents and
organocuprates on a similar pyrrolidine system; the
present authors observed similar unreactivity when
the mesylate 8 was reacted with a range of carbon
nucleophiles.
Previous work has shown that the ketone 6 is obtainable
in multigram quantities from trans-4-hydroxy-l-proline
5 in a six step sequence (Scheme 1).10 Treatment of the
{The stereochemistry, was con®rmed by deprotection of compound 7
(6M HCl(aq), Á then Dowex1 50WX8-100 ion exchange resin) and
NOED experiments on the resulting product.
xThe various thiolate salts required were prepared from their corre-
sponding thiols,13 general procedure: to a stirred solution of sodium
methoxide (1 mol equiv) in methanol was added the thiol (1 mol
equiv). After 3 h, the mixture was evaporated, the residue washed with
diethyl ether to remove excess thiol traces, and then dried in vacuo to
give the thiolate in essentially quantitative yield.
*Corresponding author. Tel.: +44-1865-275671; fax: +44-1865-
275632; e-mail: jack.baldwin@chem.ox.ac.uk
yPresent address: Department of Chemistry, Loughborough Uni-
versity, Loughborough, Leicestershire LE11 3TU, UK.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00352-8

1928
J. E. Baldwin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1927±1929
We wish to report, however, that the mesylate group of
compound 8 could be displaced by sulfur anions,
a€ording a range of 4-arylsulfanyl-substituted kainoid
analogues in protected form. For example, treatment of
the mesylate 8 with the sodium salt of 2-mercapto-1-
methylimidazole in dimethyl sulfoxide at 90 ꢀC a€orded
compound 9a in 55% yield (Scheme 2). The process was
shown to be applicable to a wider range of aromatic and
heteroaromatic thiols, as shown in Table 1.
Scheme 3. (i) 6 M HCl(aq) Á; (ii) Dowex1 50WX8-100 ion-exchange
resin.
Table 1. Reaction of the mesylate 8 with thiolates
Entry
R
Product
Yield (%)
55
1
9a
2
3
Ph
o-MeOPh
9b
9c
53
53
4
9d
47
Compounds 9a±f were treated with 6 M aqueous
hydrochloric acid at re¯ux, and then subjected to ion-
exchange chromatography (Dowex1 50WX8-100)
(Scheme 3). As indicated in Table 2, deprotected amino
acids 10a±c were obtained in good to excellent yields. In
5
6
9e
9f
53
25
Table 2. Deprotection of compounds 9a±f
Entry
R
Product
Yield (%)
77
1
10a
2
3
Ph
o-MeOPh
10b
10c
71
97
4a
10d
Ð
Scheme 1. (i) NaBH4, MeOH; (ii) MsCl, Et3N, CH2Cl2, 91% (over
two steps).
5a
10e
10f
Ð
Ð
6b
aPartial decomposition of the product occurred.
bProduct insoluble.
Scheme 2. (i) RS Na+ (5 mol equiv), Me2SO, 90 ꢀC.

J. E. Baldwin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1927±1929
1929
Acknowledgements
We thank F. Ho€mann-La Roche for ®nancial support
and Dr Andrew M. Fryer for helpful discussions.
References and Notes
1. For a review see: Parsons, A. F. Tetrahedron 1996, 52,
4149.
Figure 1. NOED spectroscopic data for compound 10a.
2. Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.;
Takemoto, T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull
1986, 34, 4892.
3. Cantrell, B. E.; Zimmerman, D. M.; Monn, J. A.; Kamboj, R.
K.; Hoo, K. H.; Tizzano, J. P.; Pullar, I. A.; Farrell, L. N.;
Bleakman, D. J. Med. Chem. 1996, 39, 3617, and references cited
therein.
cases 10d and e, where the pyrimidine and benzothiazole
functionality were susceptible to hydrolysis, isolation of
the desired material was not possible. Compound 10f
proved to be highly insoluble, making handling and
characterisation impractical.
4. For example: (a) Hashimoto, K.; Ohfune, Y.; Shirahama, H.
Tetrahedron Lett. 1995, 36, 6235. (b) Kozikowski, A. P.; Fauq,
A. H. Tetrahedron Lett. 1990, 31, 2967. (c) Goldberg, O.; Luini,
A.; Teichberg, V. I. Tetrahedron Lett. 1980, 21, 2355.
5. (a) Murakami S.; Takemoto T.; Shimizu, Z. J. Pharm. Soc.
Jpn. 1953, 73, 1026; (b) Impellizzeri, G.; Mangia®co, S.;
Oriente, G.; Piatelli, M.; Sciuto, S.; Fattorusso, E.; Magno, S.;
Santacroce, C.; Sica, D. Phytochemistry 1975, 14, 1549.
6. Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.;
Matsumoto, T. J. Am. Chem. Soc. 1988, 110, 4807.
7. Hashimoto, K.; Horikawa, M.; Shirahama, H. Tetrahedron
Lett. 1990, 31, 7047.
The stereochemistry of compound 10a was con®rmed
by NOED spectroscopic experiments, the key data from
which is presented in Figure 1. Irradiation of the signal
pertaining to 4-H enhanced the 3-H signal by 4.5% and,
conversely, irradiation of the 3-H signal enhanced the 4-H
signal by 6.5%. There was no enhancement of the 3-H
proton upon irradiation of the 2-H signal, neither was
there a through-ring interaction between 2- and 4-H.
1
Additionally, the signals in the H NMR spectrum of
the methylene group adjacent to the carboxyl group of
compounds 10a±c had a characteristic splitting pattern,
which has been observed in analogous compounds.9
8. Schneider, M.-R.; Klotz, P.; Ungureanu, I.; Mann, A.;
Wermuth, C.-G. Tetrahedron Lett. 1999, 40, 3873, and refer-
ences cited therein.
9. Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J. Bioorg. Med.
Chem. Lett. 2000, 10, 309.
10. Baldwin, J. E.; Bamford, S. J.; Fryer, A. M.; Rudolph, M.
P. W.; Wood, M. E. Tetrahedron 1997, 53, 5233.
11. Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1991,
32, 2625.
12. Barraclough, P.; Hudhomme, P.; Spray, C. A.; Young, D.
W. Tetrahedron 1995, 51, 4195.
13. Bowman, W. R.; Rakshit, D.; Valmas, M. D. J. Chem.
Soc., Perkin Trans 1 1984, 2327.
In summary, a novel class of 4-arylsulfanyl-substituted
kainoid amino acids have been synthesised from com-
mercially available trans-4-hydroxy-l-proline 5. Despite
some limitations, this route should allow the preparation
of more 4-C heteroaromatic kainoid analogues by
parallel nucleophilic substitutions on the mesylate 8.
The prepared compounds are currently undergoing bio-
logical evaluation for their use as neuropharmacological
tools for the study of kainate receptors in the CNS.